In my previous depression post, I talked about the symptoms and characterization of depression. In this one, I want to talk about what's out there to treat it.

As I covered in the last depression post, depression can come in many flavors. But no matter which type, depression can make life a living hell and cause suffering both to the patient and the people around them. Doctors have been trying to treat depression for a long time, with treatments from trepanation with many holes or cross-shaped holes (which you can find lots of info about over at Neurophilosophy) to bloodletting, though some doctors, particularly in Muslim countries, tried to treat it with soothing environments and music.
However, since about the 1950's, an assortment of drugs to treat depression has come on to the market. I'm only going to cover the four most common categories, but keep in mind that there are many more types of drugs and treatments out there, especially as research has progressed. Also keep in mind that I am NOT the expert on this topic, it's merely a subject that I find exceedingly interesting, and which I would like to study some day, but I will not say I know everything about it right now.
The Tricyclic Antidepressants
The first group of antidepressants to come into use were the tricyclics (TCAs), with Imipramine (Tofranil) as the original, and Amitryptiline (Elavil) as perhaps the most well known. Studies were first done with imipramine, when Dr. Kuhn noticed that, though the drug had no effects in psychotic patients, it worked wonders with some of his patients with severe depression. For the next 30 years, TCAs became the drug of choice for treating unipolar depression, though their side-effect profile means that they have somewhat limited efficacy.

The TCAs are norepinephrine (NE) and serotonin (5-HT) reuptake inhibitors. These chemicals are two kinds of neurotransmitters in your brain, that play a large role in the communication between neurons. When one neuron fires, it releases a neurotransmitter, such as NE, into a small space in between the first neuron and its neighbor. The transmitter crosses the space, and gets bound to receptors that are specific for it on the other side, stimulating the neighboring neuron to pass on the message. However, you don't want your neurotransmitters hanging around and stimulating, you want a short, brief pulse to get the message across. So the releasing neuron has transporters that reuptake and recycle the NE, or 5-HT, once it is released, which allows for a short signal, and also allows your brain to save energy by recycling the neurotransmitter to use again.
What TCAs do is inhibit the transporters that do the recycling, and this allows NE and 5-HT to build up in the synapse. Although the original drug itself is effective, it also has active metabolites. For example, imipramine, which has activity at both NE and 5-HT transporters is broken down to desipramine (itself a drug on the market as Norpramin), which has activity specific for NE transporters.
So when you first take a TCA, you get increases in neurotransmitters in the synapse. But this overstimulation doesn't last. Due to the high levels of neurotransmitters, your receptors on the neighboring neurons will desensitize, making them less sensitive to the high levels of neurotransmitters around. You also get a decrease in firing of NE and 5-HT neurons. However, after about three weeks of treatment, firing returns to normal levels, and this is about the time when patients begin to see results (though not everyone does see results, and differences in responsiveness may be due to genetic or other variables).Note: Scientists first thought that levels of neurotransmitters account for depressive symptoms and the effects of antidepressant medications, but now there is a new theory that anti depressant medications have long term downstream effects on neuronal growth in the brain. I'm not going to cover that here, that's for the next post. If you want some insight RIGHT NOW, check out "how prozac really works" from The Frontal Cortex).
Although TCAs were the first set of drugs discovered to treat depression, they have a significant side effect profile, so now are reserved as a secondary or tertiary line of treatment if other methods fail. Side effects include: postural hypotension (when you sit up you get dizzy), dry mouth, constipation, dizziness, sleepiness, and weight gain. Also these drugs should not be mixed with other antidepressant drugs which can increase side effects, or even other protein bound drugs (such as asprin or barbiturates) because that can interfere with their breakdown in the liver and result in potentially toxic effects.
The Monoamine Oxidase Inhibitors
The monoamine oxidase inhibitors (MAOIs, which always reminds me of M.O.A.I. in the 'love poem' from Twelfth Night, say it softly! "If I could make that resemble something in me,--Softly! M, O, A, I,--") were originally discovered in 1951, when isoniazid was developed as a treatment for tuberculosis, of all things. They found that, not only does it help the symptoms of TB, but it puts the patients in an awfully good mood, in fact causing the caretakers some trouble with discipline. It turned out that the metabolite of isoniazid, iproniazid, inhibited monoamine oxidase.
What is monoamine oxidase? Well, as you know by now, to send signals, cells release neurotransmitters into the synapse, which activate receptors on the neighboring cell and lead to the transmission of a message. Most of the neurotransmitters that are released get taken back up by transporters, but a certain number of them also get broken down into inactive parts by monoamine oxidase. Monoamine oxidase comes in two flavors, A and B, with monoamine oxidase A preferring to breakdown NE and 5-HT, while B has more of a preference for dopamine (DA). Monoamine Oxidase, image via 3Dchem.com
The clinical effects appear to mostly be due to the inhibition of MAO-A, which is selective for NE and 5-HT. Since these compounds are no longer being broken down, you get more of them in the synapse, then selective desensitization of synaptic receptors, decreases in firing, and then a return to homeostasis, much like with the TCAs. MAOIs are still on the market today, mostly as Nardil, Parmate, or Marplan. They are most often prescribed for treatment-resistant depression, because of their side effect profile and some interesting changes that have to be made to your diet.
Side effects of MAOIs include inhibitation of ejaculation, fatigue, dry mouth, hallucinations (at high doses), and excessive central stimulation (NE in particular) which can result in tremors, insomnia, agitation, and dizziness. Not only that, MAOIs have toxic interaction with compounds that contain phenylephrine or tyramine. This means that if you're on them you cannot eat: cheese, bananas, yeast, liver, smoked or pickled fish, avacados, beer, wine, or chocolate. So you can see why this drug might be a last resort.
Finally, MAOIs should not be mixed with other drugs that have an effect on the serotonin system, because really high levels of serotonin in your body can result in something called serotonin syndrome. It's a pretty rare conditioned characterized by restlessness, tremors, hyperreflexia, mental effects, myoclonus, seizures, and coma. So they cannot be mixed with TCAs or with SSRIs (which are the next topic!)
Selective Serotonin Reuptake Inhibitors
As you can tell, TCAs and MAOIs have some pretty interesting side effects associated with them, and so, though they are often effective, they can be difficult for outpatient treatment. So when the selective serotonin reuptake inhibitors (SSRIs) came on to the scene, with their low side effect profile, they skyrocketed in sales, and were soon one of the best selling drug classes in the United States. And they still are. Everyone's heard of Prozac (fluoxetine), Celexa, Lexapro (citalopram), and Zoloft (sertraline).

What's so great about SSRIs? As you can tell by their name, they inhibit the uptake of 5-HT from the synapse, in a manner similar to the TCAs. However, SSRIs are much more selective for serotonin instead of NE, and so you avoid many of the side effects associated with the TCAs. However, just because they have a safer side effect profile, doesn't mean that they are better at treating depression. Long term effects of the drug include changes in 5-HT receptors, as you would expect, though they may also include changes in brain-derived neurotrophic factor (BDNF), and changes in neurogenesis in the hippocampus.
The most common side effects of the SSRIs are highly variable, but can include nausea, headaches, sexual dysfuction, weight gain, and seizures at really high doses. There are also some indications of suicide, but I'm going to leave that part alone for right now. Also note that SSRIs increase liver microsomal oxidases, so drugs that are metabolized by liver microsomal oxidases may build up in the blood more than normal.
Until recently, the SSRIs were the gold standard in antidepressant treatment. In many cases, they still are. But some doctors are now showing a preference for even newer drugs: the atypical antidepressants.
The Atypical Antidepressants
For a while recently, the name on everyone's lips was Wellbutrin (buproprion). Closely following Wellbutrin was Buspar (buspirone), as well as Remeron (mirtazepine). What were these new drugs?
These are they atypical antidepressants. They are called atypical because they don't work in any of the ways we associate with traditional antidepressants, and yet they score well on animal tests for anti-depressant efficacy (which I may go into in one of the later posts), and also score well among patients. They are also atypical in that no single one works the same way as another.
For example, Wellbutrin is more of a stimulant than an antidepressnat, and inhibits the reuptake of DA and NE. Its metabolites may also be active. This is very different from the typical antidepressants because it does not focus on the serotonin system. In contrast, Buspar and Remeron are both agonists that stimulate specific 5-HT receptors on the neuron, increasing the effects of 5-HT at these particular receptors.
Because they are atypical, none of these drugs will have the same side effect profile, though Wellbutrin has side effects associated with stimulants (such as insomnia, weight loss, and anxiety), while Buspar and Remeron may have side effects associated with the more typical antidepressants. They may not be better antidepressants, but they often are associated with a better side effect profile and toleration.
Although all of none of these drugs may be effective, depending on the patient, they are all known to do better when the patient also has a support group and talk therapy. Combination of talk therapy and pharmacology appear to produce the best results.
Also keep in mind that after a patient has been on the drugs for a long period of time, going off them may result in withdrawal. Your body and brain have gotten used to the presence of the drugs. This does NOT mean that they are addictive, you aren't going to feel a huge drive to take them and a tendancy to sell your child for your next Prozac hit. But your body and brain will need time to adjust, so it's always best to discuss a taper off the drugs with your doctor if you want to quit. Some of the drugs are very long acting (such as Prozac, which can have a half life of several days), so decreasing over several weeks on a taper can prevent problems associated with going full turkey. When people go off antidepressant medications they can suffer depression, anxiety, headaches, nausea, weight loss or gain, and even a possibility of seizures if you've previously been on a high dose.
So that's what I know on the current pharmacotherapies. If I've said anything blatantly untrue, or if anyone has more up to date knowledge or new information, please comment! I can't learn new stuff unless I know where to find it.
Next up will be current methods of studying depression and antidepressants in the lab! But since this was a LONG post, let's wait until my fingers recover, yeah?

Good summary, Scicurious! I'm also interested in these drugs, as I've had several friends and acquaintances (and an ex-wife) who have been prescribed several of them, and I'm curious about these drugs' behavioral effects.
I have a perhaps illusory idea that when I meet someone sometimes I think I can tell if the person is on SSRIs. There's an oddness of personal affect, a certain wide-eyed brightness, which seems indicative, and sometimes I've been confirmed in my guess. Very subjective and vague, I know!

Another aspect to selection of antidepressants is overdosage, something that has to be considered in depression because of the risk of suicide. Tricyclic ODs are deadly, and very difficult to treat, requiring admission to ICU and cardiac monitoring. SSRIs are comparatively safe in overdosage. AS a pathologist, I have seen multiple deaths from tricyclic ODs but not a single one from SSRIs. I don't know the danger of MAOIs or atypicals, since these are prescribed less commonly.

SciC, I already admired you greatly but you now give me so, so much hope for the next generation of neuroscientists. Your referencing of Kuhn's 1958 Am J Psych paper brought tears to my eyes. Your mentor and committee should sign off on the PhD paperwork right now.

At the risk of sounding too stupid for the room (or, at best, desperately ignorant), what about the use of St. John's Wort for depression? I've heard everything from, "It's better than sliced bread! Shovel it right in!" to "It's useless except perhaps as a placebo, and dangerously unregulated in dosage". An informed opinion that isn't trying to sell me something would be nice. 🙂

cicely: no question is ever stupid, the worst thing would be not asking.
I don't know a great deal about St. John's Wort personally, but NCCAM (the National Center for Complimentary and Alternative Medicine) has a page on it. Their largest studies have failed to show any effect in treatment of major depression. There might be an effect for minor depression, when you don't necessarily need something much better than placebo. I would ask your doctor, though, and see what they say. It's true that many herbal remedies are not controlled with regard to dosing, and that should definitely be something you (and your doctor) take into consideration.
But make sure that, if you're taking it, you LET YOUR DOCTOR KNOW. A lot of people think that herbs and supplements "don't count", and don't tell their doctors when they are on such things. This is bad, because herbal remedies (for example, St. John's Wort), can interact and interfere with some medications you might be prescribed. St. John's Wort is known to interact with other antidepressants and birth control, for example. So make sure you're doctor knows if you're considering taking it or any other herbal things, so they can take that into account when they prescribe something.

There are two critical problems with St John's wort - one of standardization and efficacy, the second of safety and drug interactions.
Pharmaceutical grade SJW products are available in Europe and have shown antidepressant efficacy in some reasonably-powered studies. Similar trials in the US with some of the very same products have not been as successful and we really don't know why. One problem is that even in vitro neurochemical experiments do not reveal which compound or combination of compounds are necessary for potential antidepressant efficacy. So, even when SJW products are standardized for a given chemical (hypericin, hyperforin, other), there is no way to know if the antidepressant component(s) are there in reasonable concentrations or combinations, even if the product has the potential for antidepressant efficacy.
But the major reason to stay away from SJW is that one of its constitutents, hyperforin, is the most potent known inducer of the drug metabolizing enzyme, CYP3A4. This may sound like jargon, but suffice it to say that CYP3A4 is responsible for metabolizing about half of all prescription drugs, from post-organ transplant immunosuppressives and some chemotherapies to oral contraceptives and HIV protease inhibitors. By increasing the metabolism of these other drugs, SJW products can cause them to become ineffective. There are data, in people, which strongly support that these drug interactions are real - for example Swiss heart transplant recipients began rejecting their organs while taking SJW because it caused the immunosuppressant to be metabolized more rapidly (and therefore rendered less effective).
While there may be herbal products with decent efficacy and side effect profiles, SJW is not one of them - and this comes from a researcher who studies herbs and natural products for a living.
Moreover, if you have symptoms of depression, *please* do not attempt to self-diagnose. Depression is as potentially life-threatening as heart disease - seek a professional diagnosis and well-constructed treatment plan the includes the best combination of therapy and pharmaceuticals.

Excellent post, Sci! I'm eagerly awaiting your next in the series.
Somewhat sort-of related question: I am a big fan of wellbutrin as I think I have commented before. When I take it, it literally makes me not care about smoking. I recently read somewhere that the reason this happens is because it reduces the effects of nicotine in the brain - making smoking less satisfying. Do you know anything about the validity of this claim, or how that would work?

JLK, I tried wellbutrin to stop smoking and it had little, probably no effect on my desire to smoke. It's possible I'm addicted to more than the nicotine?
For me, the almost immediate and extremely noticeable plunge in the ability to concentrate was devastating. What I do not know is whether this was due to the wellbutrin or something else happening simultaneously, but it was severe enough I'll never take wellbutrin again, just in case.
Though I didn't have severe side effects with chantix, it did not reduce my desire to smoke. It did make it somewhat easier to go long periods without smoking. I'm going to give it another try as soon as I feel like jumping through the hoops to get my insurance to pay for it. The first try was out of my own pocket, so that doesn't speak well for a financial incentive 🙂
Back to SSRI's (and SNRI's)... there is a small enough difference between, say Lexapro and Celexa, that insurers will automatically choose the least costly of the two. However, they do differ. How much do these small differences matter to an individual? Is there evidence that some individuals respond better to one than the other? Also, consider Effexor and Pristiq.
Are these differences merely marketing plans or is there a clinical advantage in some people for one over the other?

I appreciate the responses to my SJW questions, and I assure you, I am not self-diagnosing/self-medicating; but my husband has been taking it for about 4-5 years for mild depression. When he first started taking it we asked the doctor we were seeing then, and she said it wouldn't hurt (in retrospect, I'm not sure whether she was thinking of it as a placebo, or that it was mild enough to cause no trouble). Since then we have changed doctors, and found that some of her treatment choices don't meet with the approval of our current doctor. Possible interference with my hubby's prescription meds is exactly the sort of thing I worry about (blood pressure and diabetes medications). Sounds like I should make a point of bringing the subject up at his next appointment.

I always just called it the Zoloft blob, but I think "depressed marshmallow" seems pretty accurate.
I am now totally facinated by isoniazid. Apparently, you can combine it with a bunch of other things and use it for malaria too; although combined studies suck for understanding mechanisms. I know somebody who will be interested to think of starving cells of NADH as a potentially viable way of killing off Plasmodium though.

As someone who knows NADA about science but has a long and icky history of depression, I believe I'm on MAOIs but my doctor's never said anything about needing to change my diet - I'm on 40mg citalopram daily - is it only very high doses which create a problem? And what would the symptoms be?

Sarah: You are not on an MAOI. Citalopram is an SSRI, a selective serotonin reuptake inhibitor, which has a much ebtter side effect profile. 40 mg is not such a high dose, so you should be ok. VERY high doses (hundreds of mg per day) coupled with other serotonin drugs could result in something called "serotonin syndrome". This is VERY rare, but symptoms would include sweating, confusion, loss of muscle tone, shivering, dilated pupils, high heart rate, and seizures. But don't worry, you're not on a dose that is anywhere close to causing these problems. If you do start to have side effects or problems that you think are associated with the drug, MAKE SURE to ask your doctor before adjusting your dose or something.
Thanks for asking!

Hi. Well I've been taking 20mg Citalopram for the last year, and I can honestly say that I have no idea whether it works or not.
One sentence about my depression - suspended from work, drink,cannabis, whoa is me, getting better, getting job back, not at all depressed now. Kind of reactive thing, I'm not usually a miserable man.
So how did Citalopram do? Dunno. And I have in the past had a thing for recreational drugs (my favourites - cannabis and ecstasy) so I am well aware of the psycho-active effects of drugs - that was why I took them.
The only thing I felt a little was that it helped when I was having anxiety attacks (well, feeling acutely miserable), possibly. Certainly no psycho-active action.
Perhaps the dose was low. Perhaps it was just a reactive depression like when a loved one dies, and the process took its course, only slightly attenuated. Or perhaps my brain thought it was a placebo.
I've recently stopped taking it, no effect, and am unlikely to want any more anti-depressants (I hope!) but if I did...ummm....is there a slightly stronger one that...makes me just feel good....like ecstasy does? I mean, we druggies could take a little more psychoactivity than most people - is there a legal one for us?

I just found your blog, but I just read through this post and I actually take a SNRI (Cymbalta), so does my mom. What is the norepinephrine role in depression? I guess I could look it up myself, but it wouldn't be as clear and well-written as what you've got here.

Andie: good question! I've got a post on the serotonin theory of depression here, but I haven't really written on norepinephrine, mostly because it's not as well studied. I'd be glad to give it a try, though! Send me an email and remind me, and I can try and do it in the next few weeks.

I found your blog through a friend posting a link to part 4 of this series, I've since gone back and am making my way through the other three entries. I'm on welbutrin and generally finding it effective. I'm also on ritalin (well, concerta, same drug, different pill design) which also (to the best of my knowledge) works on the dopamine system. Is there any research out there on why stimulant medications, while affecting the dopamine system aren't used for depression? Or is it that welbutrin is just odd, and generally mucking with (used here in a positive sense) the dopamine system doesn't do much with depression? Or is it that the effects on the norepinephrine system are what account for welbutrin's effectiveness?
Thank you for these posts. Learning more about both my brain chemistry and what I'm doing to it always makes me feel a bit better about these things.

This is for Jason:
I think most depression treatment schemes target serotonin because that is the chemical that controls persistant emotional states and moods, while the other neurotransmitters do other things. There is a pretty good reason to not mess with the dopamine system- it is linked quite strongly with addiction! Dopamine seems to be the 'reward' chemical message, and fudging with it could cause you to become addicted to whatever substance boosts either dopamine synthesis, receptor binding, decreases reuptake or directly activates the dopamine receptor. While there is some evidence that people with depression have less functional signalling of dopamine, it is a cause-effect question: is the person depressed because other biochemical imbalances (serotonin) throw everything else out of whack including dopamine and norepi? or, is dopamine disregulation causing the person to be depressed? I've seen dopamine therapies like Wellbutrin used in conjunction with other SSRI/SNRI combos in depression treatment, and the use of stimulant or activating drugs like Concerta used in conjunction with others to overcome the lethargy and lack of energy/motivation that one feels as either a side-effect of depression or other drugs used to treat it. FYI concerta acts as a norepinephrine and dopamine re-uptake inhibitor.
Hope that helps a little!

After much trial and error, my psychiatrist and I have settled on a daily regimen of Prozac, Zoloft and Ritalin, which I have been taking for quite some time now. It's hardly perfect, but it and the talk therapy have kept me walking and talking (and sometimes kinda smiling) for a while. I'm on these things long-term.
Prior to this treatment, I was in pretty bad shape psychologically and physically. I was a runner in good health otherwise, but my weight started dropping and I was nauseated and anxious all the time. This had nothing to do with classic anorexia. I'm 5'7" and dropped to about 110. (I do best at around 125.)
Now, years later, everything is much better, certainly less dire. And my weight? Has ballooned up to 150 and I cannot get it down. It's belly fat, and it is unimpressed with how much walking and hiking I do; it just stays and stays. I understand how weight gain often causes non-compliance with medication, but I'm not willing to risk the depressive symptoms. I just wish I knew more about the mechanism of weight gain with these drugs. Which is, I guess, a good reason to go read Part 3 of this series. Which I will now do. kthx

Can you add an index page for this series and/or maybe put on a link to the next and previous posts of the series? Will make browsing a little bit easier, instead of having to use the posts search engine.
Thanks!

Monica: most of the people taking Wellbutrin as a buddy to an ssri that I know do it because it often fixes the sexual side effects caused by the SSRI. I react that way to SSRI's as well and they just make me sleepy and not less depressed so I take just the Wellbutrin.

Also, I will say that big doses of Wellbutrin felt borderline recreational for the first few days. It's a good drug.